Transforming growth factory (TGF-β), as well as activin, BMP and the like, is a molecular entity belonging to a TGF-β superfamily. There are two distinct signaling receptors for TGF-β (type I and type II), both of which have serine/threonine kinase regions in their respective cells. Upon combining the TGF-β with the receptor, the type I receptor is phosphorylated by the type II receptor and thus activated, so that the signal is transferred to a nucleus via a Smad2/3 pathway or a TAB1/TAK1 pathway.
It has been apparent that the TGF-β has quite a lot of physiological actions, and as one of such actions, it has been well known that the TGF-β has a property of accumulating extracellular matrix in tissues through production stimulation and decomposition suppression of proteins which constitute the extracellular matrix (Massague, Ann Rev Cell Biol 6, 597-641 (1990)). Thus, continuous hyperproduction of TGF-β and activation of signal transduction system may lead to various fibrosing diseases. In the case of kidney, for example, TGF-β has been shown to be deeply involved in fibrosis or glomerulonephritis in renal disease such as glomerulonephritis or diabetic nephropathy (Okuda et al., J Clin Invest 86, 453-462 (1990), Border et al., Nature 346, 371-374 (1990)), and in the case of liver, TGF-β has been shown to facilitate production of extracellular matrix in the nonparenchymal cells and then contribute to the onset of hepatic fibrosis and liver cirrhosis (Barnard et al., Biochim Biophys Acta 1032, 79-87 (1990)). In addition, one of the causes of such intractable diseases as pulmonary fibrosis or proliferative vitreoretinopathy accompanied by substantial fibrosis is accumulation of extracellular matrix due to hyper function of TGF-β.
An inhibitor of ALK5 has been reported to suppress the accumulation of extracellular matrix induced by TGF-β by way of blocking TGF-β/Smad signals (Grygielko et al., ASN 2002 F-FC022), so that this inhibitor is considered to be useful as pharmaceutical products for treatment or prevention of various diseases associated with fibrosis of kidney, liver or lung, etc.
On the other hand, TGF-β is known to exhibit significant growth inhibitory action against various cells such as epithelial cells, vascular endothelial cells, hematocytes, or lymphocytes (Soma et al., J Invest Dermatol 111, 948-954 (1998)). As for hair follicles, it has been reported that TGF-β hyperexpression induces growth suppression/apoptosis in the hair follicle cells and then a hair cycle is shifted from anagen to telogen, and thus it has become apparent that TGF-β is deeply involved in progression of alopecia (Foitzik et al., FASEB J 14, 752-760 (2000)).
However, research has not fully shown that which signaling pathway from the TGF-β receptor primarily contributes to the growth suppression/apoptosis in the hair follicle cells, and thus prevention/treatment effect of alopecia which is based on blockade of TGF-β/Smad signals caused by the ALK5 inhibitor has not yet been reported.
Although substances having inhibitory action on activin receptor-like kinase 5 (ALK5) which is a TGF-β type I receptor are described in WO00/61576A, WO01/72737A, WO01/62756A, WO02/40468A, WO03/87304A and the like, a thiozolylimidazole compound according to the present invention has not been shown.
Further, although an imidazole compound having a similar structure to that of a compound according to the present invention is well known from WO99/03837A, WO96/03387A, WO03/62215A, WO01/85723A, WO01/44203A, JP2001163861A, JP07112975A, U.S. Pat. No. 6,770,663, WO04/005264A and the like, the inhibitory action of these compounds against activin receptor-like kinase 5 (ALK5) has not yet been reported.